Macrocyclic serine protease inhibitors

Abstract

Provided herein are macrocyclic serine protease inhibitor compounds, for example, of Formula Ia or Ib, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof.

What is claimed is:  
     
       1. A compound of Formula Ia or Ib: 
       
         
           
           
               
               
           
         
         or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof; 
         wherein:
 R 5  is —NHS(O) 2 R 8 ; wherein R 8  is 1-methylcyclopropyl or 1-ethynylcyclopropyl; 
 L is —O— or —OC(O)NH—; 
 
         R 6  is methoxy-fluoro-(isopropylthiazolyl)quinolinyl, methoxy-chloro-(isopropyl-thiazolyl)quinolinyl, methoxy-bromo-(isopropylthiazolyl)quinolinyl, methoxy-methyl-(isopropylthiazolyl)quinolinyl, dimethoxy-(isopropylthiazolyl)quinolinyl, difluoromethyl-chloro-(isopropylthiazolyl)quinolinyl, difluoromethyl-methyl-(isopropylthiazolyl)quinolinyl, trifluoromethyl-methyl-(isopropyl-thiazolyl)quinolinyl, methanesulfonamido-chloro-(isopropylthiazolyl)quinolinyl, methane-sulfonamido-methyl-(isopropylthiazolyl)quinolinyl, methoxy-fluoro-(trifluoromethylthiazolyl)-quinolinyl, methoxy-chloro-(trifluoro-methylthiazolyl)quinolinyl, methoxy-bromo-(trifluoromethylthiazolyl)quinolinyl, methoxy-methyl-(trifluoromethylthiazolyl)quinolinyl, dimethoxy-(trifluoromethylthiazolyl)quinolinyl, methanesulfonamido-methyl-(trifluoromethylthiazolyl)quinolinyl, methoxy-chloro-(ethenyl-thiazolyl)quinolinyl, methoxy-chloro-(ethynylthiazolyl)quinolinyl, methoxy-methyl-(ethynyl-thiazolyl)quinolinyl, methoxy-chloro-(cyanothiazolyl)quinolinyl, methoxy-chloro-(methyl-thiazolyl)quinolinyl, methoxy-chloro-(cyclopropylthiazolyl)quinolinyl, methoxy-chloro-(cyclobutylthiazolyl)quinolinyl, chloro-methoxy-(isopropyl-1H-pyrazolyl)quinolinyl, methyl-methoxy-(isopropyl-1H-pyrazolyl)quinolinyl, chloro-methoxy-(trifluoromethyl-1H-pyrazolyl)-quinolinyl, methyl-methoxy-(trifluoromethyl-1H-pyrazolyl)quinolinyl, methoxy-fluoro-(isopropylisoxazolyl)quinolinyl, methoxy-chloro-(isopropyl-isoxazolyl)quinolinyl, methoxy-bromo-(isopropylisoxazolyl)quinolinyl, methoxy-methyl-(isopropylisoxazolyl)quinolinyl, dimethoxy-(isopropylisoxazolyl)quinolinyl; and
 Q 1  is —N(R 17 )—; wherein R 17  is independently hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; 
 Q 2  has the structure of: 
 
       
       
         
           
           
               
               
           
         
         wherein:
 Y is a bond, —O—, —S—, —S(O)—, —S(O) 2 —, or —N(R Y )—, wherein R Y  is hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, —C(O)R Ya , —C(O)OR Ya , —C(O)NR Yb R Yc , —S(O) 2 NR Yb R Yc , or —S(O) 2 R Ya ; where each R Ya , R Yb , and R Yc  is independently hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-7  cycloalkyl, C 6-14  aryl, C 7-15  aralkyl, heteroaryl, or heterocyclyl; 
 q is an integer of 0, 1, 2, 3, or 4; 
 r is an integer of 0, 1, 2, 3, or 4; and 
 m is an integer of 0 or 1; and n is an integer of 1 or 2; with the proviso that the sum of m and n is 2. 
 
       
     
     
       2. The compound of  claim 1 , wherein R 17  is hydrogen or methyl. 
     
     
       3. The compound of  claim 1 , wherein R 6  is 7-methoxy-8-fluoro-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-bromo-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-methyl-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 5,7-dimethoxy-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 6-chloro-7-methoxy-2-(4-isopropyl-thiazol-2-yl)quinolin-4-yl, 6-methoxy-7-chloro-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 6-methoxy-8-methyl-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 6-methoxy-8-chloro-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-difluoromethyl-8-methyl-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-difluoromethyl-8-chloro-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 6-trifluoromethyl-8-methyl-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-trifluoromethyl-8-methyl-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-trifluoromethyl-8-chloro-2-(4-isopropyl-thiazol-2-yl)quinolin-4-yl, 7-methanesulfonamido-8-methyl-2-(4-isopropylthiazol-2-yl)-quinolin-4-yl, 7-methanesulfonamido-8-chloro-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 6-methyl-8-difluoromethyl-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-fluoro-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-bromo-2-(4-trifluoromethyl-thiazol-2-yl)quinolin-4-yl, 7-methoxy-8-methyl-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 5,7-dimethoxy-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 6-methoxy-7-chloro-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 6-methoxy-8-methyl-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 7-methanesulfonamido-8-methyl-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-ethenylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-ethynylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-methyl-2-(4-ethynylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-cyanothiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-methylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-cyclopropylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-cyclobutylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-fluoro-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 7-methoxy-8-bromo-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 7-methoxy-8-methyl-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 5,7-dimethoxy-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 6-methoxy-7-chloro-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 6-methoxy-8-methyl-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(2-trifluoromethylthiazol-4-yl)quinolin-4-yl, 7-methoxy-8-methyl-2-(2-trifluoromethylthiazol-4-yl)quinolin-4-yl, 8-chloro-7-methoxy-2-(3-isopropyl-1H-pyrazol-1-yl)quinolin-4-yl, 8-methyl-7-methoxy-2-(3-isopropyl-1H-pyrazol-1-yl)-quinolin-4-yl, 8-chloro-7-methoxy-2-(3-trifluoromethyl-1H-pyrazol-1-yl)quinolin-4-yl, 8-methyl-7-methoxy-2-(3-trifluoromethyl-1H-pyrazol-1-yl)quinolin-4-yl, 7-methoxy-8-fluoro-2-(5-isopropylisoxazol-3-yl)-quinolin-4-yl, 7-methoxy-8-chloro-2-(5-isopropylisoxazol-3-yl)quinolin-4-yl, 7-methoxy-8-bromo-2-(5-isopropylisoxazol-3-yl)quinolin-4-yl, 7-methoxy-8-methyl-2-(5-isopropyl-isoxazol-3-yl)quinolin-4-yl, 5,7-dimethoxy-2-(5-isopropylisoxazol-3-yl)quinolin-4-yl, 6-methoxy-7-chloro-2-(5-isopropylisoxazol-3-yl)quinolin-4-yl, or 6-methoxy-8-methyl-2-(5-isopropylisoxazol-3-yl)quinolin-4-yl. 
     
     
       4. The compound of  claim 1 , wherein m is 0. 
     
     
       5. The compound of  claim 1 , wherein m is 1. 
     
     
       6. The compound of  claim 1 , wherein n is 1. 
     
     
       7. The compound of  claim 1 , wherein n is 2. 
     
     
       8. The compound of  claim 1 , wherein R 8  is 1-methylcyclopropyl. 
     
     
       9. The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof or a pharmaceutically acceptable salt thereof. 
       
     
     
       10. A pharmaceutical composition comprising the compound of  claim 1 , and one or more pharmaceutically acceptable carriers. 
     
     
       11. The pharmaceutical composition of  claim 10 , further comprising a second antiviral agent. 
     
     
       12. The pharmaceutical composition of  claim 11 , wherein the second antiviral agent is selected from an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a liotoxin, acerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, or a ribozyme. 
     
     
       13. The pharmaceutical composition of  claim 11 , wherein the second antiviral agent is an interferon. 
     
     
       14. The pharmaceutical composition of  claim 13 , wherein the interferon is selected from pegylated interferon alpha 2a, interferon alfahcon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, or interferon gamma-1b. 
     
     
       15. The pharmaceutical composition of  claim 10 , wherein the composition is formulated for single dose administration. 
     
     
       16. The pharmaceutical composition of  claim 10 , wherein the composition is formulated as oral, parenteral, or intravenous dosage form. 
     
     
       17. The pharmaceutical composition of  claim 16 , wherein the oral dosage form is a tablet or capsule. 
     
     
       18. The pharmaceutical composition of  claim 10 , wherein the compound is administered in a dose of about 0.5 milligram to about 1,000 milligram daily.